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Professor Lakshminarayan Ranganath: Whole-genome sequencing to understand phenotypic heterogeneity in the AKU patient registry
- 1. Sir Archibald Garrod 1857-1936 Gregor Johann Mendel (1822 – 1884) William Bateson 1861-1926
- 3. • 448 AA polypeptide • MW 50,168 • 21 histidine and 23 tyrosine residues
- 4. Homogentisate 1,2 dioxygenase Homogentisate 4-Maleylacetoacetate Plasma HGA Urine HGA Normal 6ug/l - AKU 6mg/l 6g/24h PLASMA HGA LEVELS IN AKU ENZYME ACTIVITY IN AKU Mutations lead to inactive HGD Enzyme activity Tyrosine umol/h/g liver g/day metabolised Normal 270 1600 AKU <0.05 - Heterozygote 140 800 Bondy PK, Rosenberg LE. Metabolic Control and Disease. WB Saunders Co. 8th Edition. Alcaptonuria, 1974, pp 728-9.
- 5. ▪Located on Chromosome 3(q2) ▪55Kb long and 14 exons ▪Common mutations (P230S, V360G, M368V)
- 6. • • • •
- 7. G115R G115R G115R G361R G361R G3 61R Pedigree with two affected young siblings with Alkaptonuria
- 8. E3A L4S L4X IVS1-1G>A F10fs L25P E42A S47L R53W R58fs S59X IVS3-2G>A W60G Y61P Y62C P92T W97G W97R IVS5+1G>A IVS5+1G>T G115R L119insG C120W C120F A122V A122D G123R F136Y E143D R145X G152fs D153G IVS7+2T>C IVS7+5G>A P158R Q159H G161R E168D E168K F169L K171N E178D V181F IVS8-2A>C IVS8-1G>T S189I R197G T196fs I216T G217W IVS9-56G>A IVS9-17G>A R225H R225L F227S P230T K248R Q258P K276N G270R D291E H292R V300G S305F R321X W322R R330S M339fs G360R G361R G361A G362E M368V P370fs H371R IVS13+1G>T X446R 1 2 3 4 5 6 7 8 9 10 11 12 13 14Exon AKU sequence variations in HGD
- 9. Indel includes insertions, deletions and insertion-deletions. Others includes nonsense and no-stop mutations Summary of all Identified HGD variants (2016)
- 12. One-Stop annual service model Monthly clinics Large MDT Baseline visits: 4 days FU annual visits: 3 days UK Dept of Health funded Freely available nitisinone (Engl/Scot) ITT Long term study model Clarify Natural History Efficacy and Safety
- 13. • • • • • •
- 16. 100g of protein = 4g of Phenylalanine/3g of Tyrosine Tinti et al. Rheumatology 2011;50:271-77.
- 17. TEM AKU connective tissue
- 18. mitral pulmonary Aortic root/Valve CS Aortic wall Abd Aorta Abd Aorta
- 20. • • • • • • •
- 27. >10 fold increase post-nitisinone
- 29. • •
- 30. Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease. William Harvey
- 32. • • • •
- 33. USA: Portland: M Grompe, Ms N Paulk NIH : W Wintrone, W Gahl Spain: Dr Fernandez-Canon (Leon) Italy: Annalisa Santucci, L Tinti Poland: Histology UK:(Clinical) Royal Liverpool University Hospital: Clin Chem:L Ranganath, A Milan, A Hughes, A Davison, J Devine, J Usher, NAC Coordination: H Washington, P Drane Orthopaedics: J Davidson Rhuematology:A Daroszewska Cardiology: M Fisher ENT: M McCormick Ophthalmology: M Briggs Radiology: A Dunn Phyiotherapy: S Taylor, N Loftus Dietetics: S Judd Pain relief management: A Jones Dermatology: L West, G Sharpe Medical Photography: J Soden Clinical Gait Analysis: GJ Barton, H Shepherd, S King Nuclear Medicine: S Vinjamuri Nurses: E Luangrath, H Bygott, G Bretland Patients (and surgeons) providing surgical samples Mrs B from Sleaford and other patients R Gregory N Sireau, Lord Ward-Atherton Sponsors: NHS England Highly Specialised Services European Union National Lottery UK University of Liverpool Royal Liverpool University Hospital Swedish Orphan Research team in University of Liverpool: JA Gallagher, NP Rhodes G Bou-Gharios, J Jarvis, E Lock, H Sutherland, P Wilson, C Keenan, J Dillon, L Taylor, B Norman, J Hughes, M Khedr AM Taylor The Research Team AKU Society of the UK N Sireau OG Timmis L Harrison, C Scott R Munro E Whitley S Roberts L Powell Y Ayoob